A phase 2 study of adjuvant carboplatin plus S-1 followed by maintenance S-1 therapy for patients with completely resected stage II/IIIA non-small cell lung cancer-Japanese Northern East Area Thoracic Surgery Study Group JNETS1302 study.

BACKGROUND: The standard adjuvant chemotherapy regimen for completely resected pathological stage II/IIIA non-small cell lung cancer (NSCLC) is four courses of cisplatin plus vinorelbine. However, the continuity and toxicity of cisplatin-based regimens remain problematic. Conversely, carboplatin-based chemotherapy is a less toxic and more tolerable regimen for various stages of NSCLC. In particular, the efficacy and tolerability of carboplatin plus S-1 in advanced NSCLC were confirmed by previous pivotal studies such as the LETS trail. Therefore, this phase II study assessed the feasibility, safety, and usefulness of carboplatin plus S-1 followed by maintenance S-1 as an adjuvant treatment. METHODS: In this single-arm, multicenter phase II study, 40 patients who previously underwent complete resection of NSCLC were enrolled from November 2013 to January 2015. The chemotherapy protocol was four cycles of carboplatin (AUC 5 on day 1) and oral S-1 (80 mg/m2 every other day from days 1 to 21) followed by oral S-1 (80 mg/m2 every other day for 48 weeks). The primary endpoint was the treatment completion rate, and the secondary endpoints were adverse events and 2-year recurrence-free survival. RESULTS: The treatment completion rate of the planned schedule was as low as 30.0% (90% confidence interval: 40.3-63.0%). The reasons for adjuvant chemotherapy discontinuation were adverse events, refusal, tumor recurrence, and other reasons in 13, 6, 10, and 2 patients, respectively. The 2-year progression-free survival rate was 66.7% among patients who completed maintenance chemotherapy. There were no treatment-related deaths, and most adverse events were less than grade 3. CONCLUSIONS: Carboplatin plus S-1 followed by S-1 maintenance for 1 year in the adjuvant treatment of NSCLC was not tolerable, although most adverse events were not severe. However, patients who can fully complete the regimen might experience clinical benefit.

Growth inhibition of KRAS­ and EGFR­mutant lung adenocarcinoma by cosuppression of STAT3 and the SRC/ARHGAP35 axis.

The need for effective treatment of KRAS­mutant lung cancer is an emerging issue. Rho GTPase­activating protein 35 (ARHGAP35) is reported to be a possible molecular target for lung adenocarcinoma. We investigated the effect of long­term ARHGAP35 suppression on the proliferation, migration and molecular dynamics of lung adenocarcinomas harboring KRAS and EGFR gene mutations. Lung adenocarcinoma cell lines A549 (KRAS­mutant) and PC9 and H1975 (EGFR­mutants) were used, and ARHGAP35 knockdown was carried out using puromycin. Cell viability, migration and molecular dynamics were assayed 1 month after introducing small hairpin RNA. The compensatory upregulated mechanism was screened by western blotting and confirmed by a specific inhibitor. Finally, we tested the effects of cosuppression of the SRC/ARHGAP35 axis and the identified pathway in vitro. ARHGAP35 suppression was attenuated by long­term knockdown of the target genes. Compensatory mechanisms by SRC and STAT3 caused attenuation in A549 cells. After long­term ARHGAP35 knockdown, both A549 and PC9 cells were more sensitive to treatment with a STAT3 inhibitor. The suppressive effect of ARHGAP35 knockdown on migration was sustained, but only modest, in all cell lines. Synergistic and strong growth inhibition was observed with concomitant use of an SRC inhibitor and a STAT3 inhibitor in A549 cells. STAT3 activation compensated for ARHGAP35 knockdown in lung adenocarcinoma with the KRAS mutation. Moreover, cosuppression of the STAT3 pathway and SRC/ARHGAP35 axis may be an effective strategy for treating lung adenocarcinoma, especially in the presence of a KRAS mutation.

Innervation of the Human Incisive Papilla: Comparison with Other Oral Regions.

Immunohistochemistry for several neurochemical substances was performed on the human incisive papilla and other oral structures. Sodium channel alpha subunit 7 (SCN7A) protein-immunoreactive (IR) Schwann cells and protein gene product 9.5 (PGP 9.5)-IR nerve fibers made nerve plexuses beneath the epithelium of the palate, including the incisive papilla, tongue, and lip. SCN7A immunoreactivity could also be detected in lamellated and nonlamellated capsules of corpuscle endings. Lamellated SCN7A-IR corpuscle endings were mostly restricted to the mucous and cutaneous lips. These endings had thick and spiral-shaped PGP 9.5-IR axons without ramification. Nonlamellated SCN7A-IR corpuscle endings were most numerous in the incisive papilla among the oral regions. On the basis of axonal morphology, the nonlamellated endings were divided into simple and complex types. PGP 9.5-IR terminal axons in the simple type ran straight or meandered with slight ramification, whereas those in the complex type were densely entangled with abundant ramification. Substance P (SP)-, calcitonin gene-related peptide (CGRP)-, and transient receptor potential cation channel subfamily V member 2 (TRPV2)-IR varicose fibers were rarely seen beneath the epithelium of oral structures. The present study indicates that the human incisive papilla has many low-threshold mechanoreceptors with nonlamellated capsules. SP-, CGRP-, and TRPV2-containing nociceptors may be infrequent in the incisive papilla and other oral regions.

Serum ß-hCG as an Indicator of Recurrence After the Complete Resection of a Malignant Solitary Fibrous Tumor of the Pleura.

In solitary fibrous tumors (SFTs) of the pleura, malignant SFTs are uncommon. Although SFTs are known to cause paraneoplastic syndromes through the production of insulin-like growth factor, to the best of our knowledge, the production of beta-human chorionic gonadotropin (ß-hCG) has been reported only in 1 case involving a patient with a benign SFT. We herein report the first case of the elevation of ß-hCG serum levels associated with a malignant SFT in which the ß-hCG serum level became a useful indicator of recurrence after the complete resection of the primary mediastinal lesion.

[Effectiveness of a Simulation of the Donor Surgery with Other Extraction Teams to Improve Various Problems in Pulmonary Extraction from a Brain-dead Donor].

The pulmonary extraction from a brain-dead donor is one of the important elements for the success of lung transplantation, but the current scarcity of practical training opportunities is a major problem. We performed a simulation of the donor surgery of multiple organs using a pig with other extraction teams to provide more training opportunities. The effectiveness of this simulation lies in its potential to improve the surgical procedure;furthermore, it may solve problems associated with communicating with other extraction teams. However, it is difficult to judge whether the donor lung is suitable for transplantation, as it would be inappropriate to use such a lung for simulation in training. Since this simulation system is considered to be effective to solve various problems in the current donor surgery, it should be available more frequently to improve a technical level of the donor surgery and to aid surgeons in the rapid implementation of next-generation techniques.

[Perioperative management of lung cancer patients with cardiovascular complications].

Lung cancer patients with cardiovascular complications often require antithrombotic therapy. In this study, we discuss the present conditions and future problems associated with the perioperative management of such patients. We examined 36 lung cancer patients undergoing surgery who received antithrombotic therapy for cardiovascular complications. Twenty-one patients were administered unfractionated heparin in the perioperative period (heparin group). Fifteen patients were not administered unfractionated heparin in the perioperative period (no-heparin group). No significant intergroup differences were observed in operating time, intraoperative blood loss, duration of chest tube placement, and the number of hospitalization days. However, 2 serious cases of thromboembolism developed after surgery. One was a case of pulmonary thromboembolism and the other was one of superior mesenteric artery thromboembolism. These results suggest that the appropriate perioperative usage of heparin enables the standard surgical treatment of lung cancer patients with cardiovascular complications. We recommend the use of low-molecular-weight heparin or low-dose unfractionated heparin as the antithrombotic agent after lung cancer surgery.

Adjuvant chemotherapy for resected early-stage non-small cell lung cancer.

BACKGROUND: To evaluate the effects of administering chemotherapy following surgery, or following surgery plus radiotherapy (known as adjuvant chemotherapy) in patients with early stage non-small cell lung cancer (NSCLC),we performed two systematic reviews and meta-analyses of all randomised controlled trials using individual participant data. Results were first published in The Lancet in 2010. OBJECTIVES: To compare, in terms of overall survival, time to locoregional recurrence, time to distant recurrence and recurrence-free survival:A. Surgery versus surgery plus adjuvant chemotherapyB. Surgery plus radiotherapy versus surgery plus radiotherapy plus adjuvant chemotherapyin patients with histologically diagnosed early stage NSCLC.(2)To investigate whether or not predefined patient subgroups benefit more or less from cisplatin-based chemotherapy in terms of survival. SEARCH METHODS: We supplemented MEDLINE and CANCERLIT searches (1995 to December 2013) with information from trial registers, handsearching relevant meeting proceedings and by discussion with trialists and organisations. SELECTION CRITERIA: We included trials of a) surgery versus surgery plus adjuvant chemotherapy; and b) surgery plus radiotherapy versus surgery plus radiotherapy plus adjuvant chemotherapy, provided that they randomised NSCLC patients using a method which precluded prior knowledge of treatment assignment. DATA COLLECTION AND ANALYSIS: We carried out a quantitative meta-analysis using updated information from individual participants from all randomised trials. Data from all patients were sought from those responsible for the trial. We obtained updated individual participant data (IPD) on survival, and date of last follow-up, as well as details of treatment allocated, date of randomisation, age, sex, histological cell type, stage, and performance status. To avoid potential bias, we requested information for all randomised patients, including those excluded from the investigators' original analyses. We conducted all analyses on intention-to-treat on the endpoint of survival. For trials using cisplatin-based regimens, we carried out subgroup analyses by age, sex, histological cell type, tumour stage, and performance status. MAIN RESULTS: We identified 35 trials evaluating surgery plus adjuvant chemotherapy versus surgery alone. IPD were available for 26 of these trials and our analyses are based on 8447 participants (3323 deaths) in 34 trial comparisons. There was clear evidence of a benefit of adding chemotherapy after surgery (hazard ratio (HR)= 0.86, 95% confidence interval (CI)= 0.81 to 0.92, p< 0.0001), with an absolute increase in survival of 4% at five years.We identified 15 trials evaluating surgery plus radiotherapy plus chemotherapy versus surgery plus radiotherapy alone. IPD were available for 12 of these trials and our analyses are based on 2660 participants (1909 deaths) in 13 trial comparisons. There was also evidence of a benefit of adding chemotherapy to surgery plus radiotherapy (HR= 0.88, 95% CI= 0.81 to 0.97, p= 0.009). This represents an absolute improvement in survival of 4% at five years.For both meta-analyses, we found similar benefits for recurrence outcomes and there was little variation in effect according to the type of chemotherapy, other trial characteristics or patient subgroup.We did not undertake analysis of the effects of adjuvant chemotherapy on quality of life and adverse events. Quality of life information was not routinely collected during the trials, but where toxicity was assessed and mentioned in the publications, it was thought to be manageable. We considered the risk of bias in the included trials to be low. AUTHORS' CONCLUSIONS: Results from 47 trial comparisons and 11,107 patients demonstrate the clear benefit of adjuvant chemotherapy for these patients, irrespective of whether chemotherapy was given in addition to surgery or surgery plus radiotherapy. This is the most up-to-date and complete systematic review and individual participant data (IPD) meta-analysis that has been carried out.

Inter-rater agreement of sputum cytology for lung cancer screening in Japan.

BACKGROUND: To compare lung cancer detection rate by sputum cytology, we need some assurance that the estimates do not vary widely if different observers evaluate the same specimens. The aim of this study was to determine inter-rater agreement of sputum cytology diagnoses. METHODS: Slides of sputum cytology from 150 subjects were selected from a pool of slides held by six of the laboratories that had participated in a population-based lung cancer screening program over the last ten years in Japan. The cytotechnologists in these laboratories had considerable experience with sputum cytology. Each case was re-evaluated six times. Cases that were diagnosed as the same category by all six laboratories were selected as consensus cases to serve as standardized sputum cytology cases. Thirty-seven cytotechnologists with various levels of experience in sputum cytology then re-evaluated these consensus cases. Inter-rater agreement was calculated by kappa statistics including Fleiss' kappa. RESULTS: All pairs of interlaboratory agreement for the 150 cases showed statistically significant kappa values, most pairs showing substantial agreement. Fleiss' kappa value across the six laboratories was 0.5. Fourteen cases were identified as the consensus cases, and the agreement among observers with less experience of sputum cytology showed significantly lower than the agreement among those with considerable experience (Fleiss' kappa value 0.27 vs. 0.45, P < 0.05). Moreover, cytotechnologists with less experience under-diagnosed the slides significantly more often than those with considerable experience. CONCLUSION: When the observers have considerable experience with sputum cytology, inter-observer agreement is good.

Anterior gradient 2 is correlated with EGFR mutation in lung adenocarcinoma tissues.

BACKGROUND: Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) has demonstrated a promising therapeutic response in lung adenocarcinoma patients with EGFR gene mutations. However, the predictive factors for this therapy have not been established, except for the EGFR gene mutation status of carcinoma cells. METHODS: We first performed microarray analysis in EGFR-TKI-sensitive lung adenocarcinoma cell lines. The results indicated anterior gradient 2 (AGR2) as a potential surrogate marker of EGFR-TKI. Therefore, we then evaluated the correlation between the status of AGR2 immunoreactivity and clinicopathological factors including overall survival (OS), progression-free survival (PFS) and clinical response to EGFR-TKI, in 147 cases of surgically resected lung adenocarcinoma. The biological significance of AGR2 was further evaluated by transfecting small interfering RNA (siRNA) against AGR2 in these cells. RESULTS: The status of AGR2 immunoreactivity was significantly higher in lung adenocarcinoma cases with EGFR gene mutations than in those with the wild type (p<0.0001), but there were no significant differences in OS, PFS and response of EGFR-TKI between the AGR2 high and low carcinoma cases. Knockdown of AGR2 gene expression following siRNA transfection resulted in a significantly lower response to EGFR-TKI in EGFR-mutated PC-3. CONCLUSIONS: AGR2 could serve as an adjunctive surrogate protein marker possibly reflecting EGFR gene mutations in lung adenocarcinoma patients. Results from in vitro analysis indicated that AGR2 could be a potential clinical biomarker of EGFR-TKI therapeutic sensitivity in lung adenocarcinoma cells.

Successful bilateral lung transplantation after 16 h of lung preservation with EP-TU solution: report of a case.

We report a case of bilateral lung transplantation (BLT) after preservation of the donor graft for 16 h 5 min with EP-TU, an extracellular phosphate-buffered lung preservation solution. The recipient was a 26-year-old woman with idiopathic pulmonary arterial hypertension and the graft ischemic time was prolonged significantly because of the time required to induce peripheral veno-arterial extracorporeal membrane oxygenation (V-A ECMO) under local anesthesia, and address the severe intrathoracic and pericardial adhesions from past surgery for partial anomalous pulmonary venous return, with concurrent annular plication of the tricuspid valve. After the operation, ECMO and continuous hemodiafiltration were started preemptively to protect the grafts against excessive edema. Postoperative chest X-ray showed diffuse bilateral infiltrates, which improved within a few days and she was weaned off ECMO on day 9. Successful BLT after a graft ischemic time of over 16 h has rarely been described in clinical lung transplantation.

[Contribution of surgical margin for surgical outcome of the chest wall tumors].

We present here our institutional review of surgical treatment for the chest wall tumors. Chest wall resections were performed on 80 patients, and subsequent chest wall reconstructions were performed on 45 patients. Primary malignant tumors in the chest wall required more extensive rib resections combined with the neighboring structures such as the sternum and the vertebral bones than benign or metastatic/recurrent tumors did. Postoperative mortality and morbidity occurred in 5 patients who underwent the sternal resection and the rib resection combined with the vertebral bodies. Primary malignant tumors in the chest wall are sarcomas originating from the bones, the cartilage tissues, and the soft tissues of the chest wall. We general thoracic surgeons may not have expertise in treating sarcomas,because primary malignant chest wall tumors are rare and a single institution has limited experiences in surgical treatment of such tumors. We should be aware that a surgical margin of primary malignant chest wall tumors is important to achieve excellent local control and better prognosis. We recommend cooperation with an orthopedic oncologist who is experienced with treating sarcomas. Not only preoperative planning but also intraoperative evaluation for the surgical margin with orthopedic oncologists is necessary for better surgical outcome.

A prospective study of surgical procedures for patients with oligometastatic non-small cell lung cancer.

BACKGROUND: Purely localized, oligometastatic, and widely metastatic tumors are likely to require different therapeutic strategies. Although surgical procedures for isolated pulmonary, brain, or adrenal metastases from lung cancer have been extensively evaluated, most data are from retrospective studies; accordingly, we conducted a prospective multicenter trial. METHODS: Patients were eligible if they had previously untreated clinical T1-2N0-1 lung cancer with single-organ metastasis, or single-organ metachronous metastasis after complete resection of pathologic T1-2N0-1 lung cancer. Metastatic lesions were classified into three groups: group A included metastasis in single organs other than brain or lung; group B included synchronous brain metastasis; and group C included pulmonary metastasis. The treatment intervention was surgical resection of metachronous metastasis or of both synchronous metastasis and primary lung cancer. RESULTS: From December 2002 through June 2011, 36 patients were enrolled. Two patients were ineligible, and the remaining 34 were analyzed; 6 (18%) had a benign lesion and no metastasis, 5 patients (15%) underwent incomplete resection of primary lung cancer, and 20 patients (59%) underwent complete resection of both primary lung cancer and metastasis. The 5-year survival rate for these 20 cases was 44.7%. CONCLUSIONS: Clinical T1-2N0-1 lung cancer with a single-organ metastatic lesion was a good candidate for surgical resection. A 5-year survival rate of about 40% can be expected, which could be comparable with that for stage II non-small cell lung cancer.

The prognostic significance of eukaryotic elongation factor 1 alpha-2 in non-small cell lung cancer.

BACKGROUND: Eukaryotic elongation factor 1 alpha-2 (eEF1A2) has been recently shown to be a putative oncogene of lung cancer. MATERIALS AND METHODS: We analyzed the expression and prognostic significance of eEF1A2 in 69 primary non-small cell lung cancer (NSCLC) cases. We also suppressed eEF1A2 expression using RNA interference and then analyzed cell proliferation, migration and invasion of five adenocarcinoma cell lines. RESULTS: eEF1A2 protein expression was positive in 84.1%. Negative immunostaining for eEF1A2 was shown to be an independent prognostic factor and significantly correlated with lymph node metastasis. There was no significant correlation between eEF1A2 protein and mRNA expression levels. Among the five examined cell lines, transfection of eEF1A2 siRNA inhibited cell migration in only one cell line while it did not change cell proliferation and invasion. CONCLUSION: Negative immunostaining of eEF1A2 predicted for poor prognosis of NSCLC. The mechanism of this result could not be elucidated by cell proliferation, migration and invasion assays.

p190A RhoGAP is involved in EGFR pathways and promotes proliferation, invasion and migration in lung adenocarcinoma cells.

Overcoming acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR­TKIs) is an emerging issue in lung cancer treatment. We report evidence that a GTPase-activating protein, p190-A RhoGAP (p190), is a potential molecular target for the treatment of lung adenocarcinoma. We documented inhibition of phosphorylation of p190 by EGFR-TKI treatment in lung adenocarcinoma cell lines. Small interfering RNA-mediated knockdown of p190 leads lung adenocarcinoma cells to growth suppression and to inhibition of invasion/migration through inducing cell cycle arrest but not apoptosis. These findings were observed not only in EGFR-TKI-sensitive cells but also in EGFR-TKI-resistant cells; even in cell lines harboring K-ras mutations. The mechanism of this inhibitory effect on growth and invasion/migration was Ras inactivation through disrupting the p190-A RhoGAP/p120RasGAP complex. In addition, a high level of p190 mRNA expression was observed in majority of surgically obtained tissue from lung adenocarcinoma patients. Overexpression of p190 mRNA associated with poor disease-free survival. The results suggest that overexpression of p190 mRNA may be involved in the carcinogenesis of lung adenocarcinoma. These findings indicate that p190 is a possible molecular target for treatment of lung adenocarcinoma.

Reconstruction of pulmonary artery with donor aorta and autopericardium in lung transplantation.

A 44-year-old man with Eisenmenger's syndrome due to ventricular septal defect (VSD) was listed for lung transplantation. The patient's condition was complicated by a giant pulmonary artery (PA) aneurysm. Concurrent VSD closure and total reconstruction of the recipient PA with the donor aorta were planned. When the patient underwent bilateral lung transplantation, the aortic graft obtained turned out to be too short to complete the reconstruction. A PA graft made of the recipient's pericardium was successfully interposed between the donor's PA and the donor's aortic graft.

Successful management of intractable chylothorax in Gorham-Stout disease by awake thoracoscopic surgery.

Gorham-Stout is an extremely rare disease, which is characterized by proliferation of vascular and lymphatic bone structures. A 15-year-old male patient was the diagnosis of Gorham-Stout disease of the cervical spine with chylothorax. Awake thoracoscopic ablation was performed using bronchoscopic tools and awake thoracoscopic debridement of the thoracoscopic cavities and chemical pleurodesis with OK-432 were repeated. The amount of drained liquid was controlled. There was no recurrence of pleural effusion.

Presented at the 64th Annual Scientific Meeting of the Japanese Association for thoracic surgery: wet-lab training for thoracic surgery at the laboratory animal facilities.

OBJECTIVE: The purpose of this study was to describe the animal thoracic training program for the thoracic surgery at the laboratory animal facilities METHOD: The training was provided for 78 surgical students under the direction of thoracic medical specialists. Students attended lectures and then performed venipuncture, injection, intubation, tracheostomy, surgical cut-down, and thoracic and abdominal surgical approaches. We estimated the detailed surgical skills in two groups (67 residents and 11 thoracic fellows). RESULTS: All students demonstrated satisfactory impressions after training. We found significant difference between the skills of residents and fellows with regard to the haemostasis and suturing techniques. CONCLUSIONS: Wet-lab training for thoracic surgery at the laboratory animal facilities is useful for surgical residents and thoracic fellows.

Early central airways lung cancer.

Early central airways lung cancer accounts for very small percentage of all lung cancers. Given this fact, it is much difficult to carry out a prospective randomized comparative clinical trial. Even retrospective studies can offer important information. Early central airways lung cancer is usually detected by sputum cytology. If sputum cytology shows atypical epithelial cells implying malignancy, the next thing we have to do is bronchoscopy. Both autofluorescence bronchoscopy and white light bronchoscopy were superior to white light bronchoscopy alone in detecting this type of lung cancer. Natural history of this cancer showed about the two-thirds of the patients die from original disease within 10 years. If the tumor length is 10 mm or less, photodynamic therapy is a first-line modality. After photodynamic therapy, a 5-year overall survival of about 80 % and a 10-year overall survival of 70 % can be expected. If a cancer does not meet the criteria for photodynamic therapy, surgical resection is recommended, and 5-year overall survival of about 80 % can be expected. Segmentectomy should be considered because of pulmonary function preservation if a tumor is located at segmental bronchi or beyond it. The frequency of multicentricity is high. Treatment strategy for subsequent primary lung cancer is an important key for the prognosis of patients with treated early central airways lung cancer. Surgical resection is still the most reliable treatment of subsequent primary lung cancer, except for in situ or microinvasive carcinoma located centrally, which could be cured by photodynamic therapy.

Completely resected superior sulcus tumor and vascular reconstruction of vertebral and subclavian arteries.

A 62-year-old man was pointed out the superior sulcus tumor of the left lung invading to the subclavian artery and the vertebral artery. Bronchoscopic brushing cytology of the tumor showed Class V large cell carcinoma. The patient was diagnosed as clinical stage IIIA(cT4N0M0). After concurrent chemoradiotherapy, we performed left-upper lobectomy and reconstructions of left subclavian and vertebral arteries through modified transmanubrial approach. Surgeons of three different departments took part in the operation. Cooperative works were the key for the complete resection of such an advanced superior sulcus tumor.

Results of long-term follow-up of patients with completely resected non-small cell lung cancer.

BACKGROUND: In patients with completely resected non-small cell lung cancer, recurrence-free survival, postrecurrence survival, and metachronous primary lung cancer have not been well studied at the same time. METHODS: A total of 315 patients with non-small cell lung cancer who underwent complete resection between 2001 and 2005 were examined. Patients were routinely assessed with computed tomography of the chest and physical checkups every 4 months for the first 2 years and every 6 months from the third to the fifth year. After that, they were examined annually. RESULTS: The overall 5-year survival was 70%. Of all 315 patients, 107 had recurrent disease. The median recurrence-free survival was 15.7 months. Multivariate analysis showed that pathologic stage and pleural invasion were associated with decreased recurrence-free survival. The median postrecurrence survival was 18.7 months. Multivariate analysis indicated that male sex, pleural invasion, extrathoracic recurrence, and supportive care for recurrence were associated with decreased postrecurrence survival. The cumulative rate of metachronous primary lung cancer at 5 years was 3.7%, and it developed even 8 years after the initial operation. CONCLUSIONS: Only pleural invasion of the original lung cancer was related to both recurrence-free survival and postrecurrence survival. Moreover, postrecurrence survival was related to both site and treatment of the initial recurrence. The incidence of metachronous primary lung cancer was stable over time after the initial operation.